The most common reason for failure in the therapy of retinal detachment or open globe injuries is the proliferation and contraction of cellular membranes that form in the vitreous cavity, termed proliferative vitreoretinopathy (PVR) (Pastor, J. C. Surv Ophthalmol 43:3-18 (1998)). It is estimated that PVR occurs as a complication of up to 5-20% of cases of rhegmatogenous retinal detachment (Pastor, J. C. Surv Ophthalmol 43:3-18 (1998); Pastor, J. C. et al., Prog Retin Eye Res 21:127-44 (2002)). In ocular trauma, the risk of PVR is very high. A review of veterans who had suffered ocular trauma with intraocular foreign bodies in Iraq during the years 2003-2005 revealed PVR as the cause for poor vision in 21% of the patients. (Colyer M. H. et al., Ophthalmology. 2007 August; 114(8):1439-47).
Clinical studies have identified multiple risk factors for the development of PVR, including vitreous hemorrhage, intraocular gas, large or long-standing retinal detachments, and surgical failures, especially if they are associated with extensive use of cryotherapy or photocoagulation (Pastor, J. C. Surv Ophthalmol 43:3-18 (1998); Pastor, J. C. et al., Prog Retin Eye Res 21:127-44 (2002)). It is possible that the extent of ocular/retinal damage leads to increased cytokine production or other signaling to cause increased PVR. Proinflammatory cytokines (for example IL-8 and MCP-1) and IL-1, IL-6, TNF-α, and IFN-γ have been found to be increased in PVR, however, cytokine levels do not directly correlate with PVR severity (Asaria, R. H. Compr Ophthalmol Update 7:179-85 (2006)).
The retinal pigment epithelium (RPE) is believed to be one of the critical cell types implicated in PVR. Pathogenesis underlying PVR is complex; however it is likely that, following trauma or retinal detachment, RPE cells are released into the vitreous or are stimulate to migrate from their subretinal location. These cells then migrate, proliferate, de-differentiate, and undergo an epithelial to mesenchymal transformation (EMT), to help create the preretinal membranes of PVR (Asaria, R. H. Compr Ophthalmol Update 7:179-85 (2006)). It is likely that the RPE cells produce membrane contraction that generates a tractional force that often lead to recurrent retinal detachments and additional vision loss (Pastor, J. C. et al., Prog Retin Eye Res 21:127-44 (2002); Kroll, P. et al., Ophthalmologica 221:78-94 (2007)).
While EMP2 has been found to be highly expressed in RPE cells, its function is only beginning to be understood (Wadehra, M. et al., Exp Mol Pathol 74:106-12 (2003)). As a member of the tetraspanin family (CD9, CD53, CD81, CD82) modulation of integrin and other cell surface receptors is common. EMP2 has been previously shown to be important in regulating cellular contractile capacity through facilitating the activation of the FAK.Src signaling complex (Morales, S. A. et al., Exp Eye Res 85:790-8 (2007); Morales, S. A. et al., Invest Ophthalmol Vis Sci 50:462-9 (2009)). In addition, activation of the FAK/Src complex has been proven to be through the physical association between EMP2 and the FAK/Src complex (Morales, S. A. et al., Invest Ophthalmol Vis Sci 50:462-9 (2009)). These in vitro studies found that EMP2 and the FAK/Src signaling complex were critical components in RPE mediated gel contraction.
Although we report here that the RPE cells are concordant in both in vivo and in vitro studies, there are many potential differences between the previously reported observations and the present investigation. First, the in vitro studies use collagen as scaffold for the RPE cells where as the RPE cells in the in vivo vitreous is exposed to hyaluronic acid and many collagen types including II, V/XI, and IX. In addition, there are many cell types that contribute to the PVR membrane in vivo including inflammatory cells, Mueller cells, fibroblast etc. (Pastor, J. C. Surv Ophthalmol 43:3-18 (1998); Pastor, J. C. et al., Prog Retin Eye Res 21:127-44 (2002); Asaria, R. H. Compr Ophthalmol Update 7:179-85 (2006); Kim, I. K. et al. Ophthalmol Clin. North Am 15:81-6 (2002)). In vivo, during PVR membrane formation, the cells are known to be exposed to many cytokines, and pre-retinal membranes have been found to contain cytokines including: vascular endothelial growth factor (VEGF), (PDGF), IL-6, IL-8, TNF-alpha, TGF-beta etc. (Harada, C. et al., Prog Retin Eye Res 25:149-64 (2006)). These cells and the milieu of cytokines made by these cells will certainly influence the cell and membrane behavior.
Today, despite surgical advances, patients too frequently lose vision secondary to PVR and tractional pre-retinal membranes. This invention meets a need for the treatment and/or prevention of retinal detachments associated with PVR.